Obesity, insulin resistance and associated metabolic abnormalities leading to increased risk of development of type 2 diabetes is best known by the term metabolic syndrome. Obesity and type 2 diabetes have reached epidemic levels in the United States and patients served by the Veterans Affairs Health Care System. These conditions are responsible for increased morbidity, reduced quality of life, and increased health care costs. Currently, there is no effective treatmen for the complications associated with obesity and type 2 diabetes. Even though studies have led to new therapies to improve insulin sensitivity this approach only delays the onset of complications. Since complications are ultimately responsible for the increased morbidity and poor quality of life in patients with type 2 diabetes there is an urgent need for development of therapies that can prevent or reduce their impact. Our proposed studies will provide preclinical evidence of efficacy and insight to mechanisms of Ilepatril, a vasopeptidase inhibitor that simultaneously blocks angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) activities, treatment for insulin resistance and vascular complications associated with obesity and type 2 diabetes. In the last 5 years we made significant progress in determining the role of ACE and NEP in the development of vascular and neural complications associated with obesity and diabetes. We have also characterized the vascular and neural complications in the high fat diet/low dose streptozotocin treated rat, an interesting model for type 2 diabetes. In the present proposal we will extend these studies and examine the ability of Ilepatril to act as a treatment fo obesity and/or reverse insulin resistance and vascular complications caused by obesity and type 2 diabetes in vivo. The central hypothesis to be explored is that obesity and type 2 diabetes up-regulate ACE and NEP expression/activity in tissues sensitive to insulin resistance and prone for complications related to obesity and diabetes leading to impaired glucose tolerance and vascular dysfunction. We propose that by targeting preservation of vascular function Ilepatril treatment of diet induced obese rats will: 1) reduce oxidative stress in vascular tissue and protect vasoactive peptides from degradation leading to improved vascular function, 2) improve glucose utilization in the whole animal, and 3) improve blood flow in skeletal muscle thereby improving insulin action and glucose uptake. We believe that treatment of obese rats after the onset of hyperglycemia (type 2 diabetes) will be less effective and may require a more comprehensive and aggressive treatment strategy to reduce the impact of complications. Specific Objectives: Objective 1: Determine whether treatment of diet induced obese rats with Ilepatril improves insulin sensitivity and vascular dysfunction in feed arteries of gastrocnemius and soleus muscle by reducing oxidative stress and protecting vasoactive peptides to a greater extent than monotherapies that block ACE or NEP alone. Objective 2: Determine whether type 2 diabetes reduces the benefits of Ilepatril treatment due to higher levels of oxidative stress and/o degradation of vasoactive peptides.